Brain metastases occur in 20-40% of advanced stage cancers and represent the most prevalent intracranial malignancy in adults (Gavrilovic and Posner, 2005; Maher et al., 2009). Lung and breast cancers are the most common sources. Despite treatment advances at other metastatic sites, current clinical management of brain metastases affords limited disease control and most patients succumb to tumor progression less than twelve months after diagnosis (Gavrilovic and Posner, 2005; Stelzer, 2013). The mechanisms underlying this disease process must therefore be understood so that they may be parlayed into rational therapeutic strategies.
The brain's unique microenvironment poses a formidable barrier to metastatic cancer cells. Recent progress has begun to unravel the complex cellular and molecular interactions responsible for the initiation of brain metastases. Circulating cancer cells that mechanically lodge in brain capillaries must first traverse the reinforced vessel walls that constitute the blood-brain barrier (BBB) (Eichler et al., 2011). Genes have been identified that mediate cancer cell extravasation through the BBB in experimental models and predict brain metastasis in the clinic (Bos et al., 2009; Li et al., 2013). Once inside the brain parenchyma, metastatic cells remain associated with the microvasculature (Kienast et al., 2010; Lorger and Felding-Habermann, 2010). Expression of the cell adhesion molecule L1CAM in the cancer cells mediates their tight adhesion to the abluminal capillary basal lamina as a requirement for the initiation of metastatic outgrowth (Valiente et al., 2014). Wnt is one of the signaling pathways supporting the outgrowth (Nguyen et al., 2009). However, the vast majority of cancer cells that infiltrate the brain perish (Chambers et al., 2002; Heyn et al., 2006; Kienast et al., 2010), and they are rejected by the most abundant cell type in the brain, the astrocyte (Valiente et al., 2014).
Functionally pleiotropic, astrocytes maintain the BBB, orchestrate neurovascular coupling, sustain homeostasis of a tissue under stringent metabolic demands (Oberheim et al., 2012) and react acutely against disturbances like injury or infiltrating cells (Pekny and Nilsson, 2005). Reactive astrocytes generate plasmin, which mobilizes the pro-apoptotic cytokine FasL to kill infiltrating cancer cells (Valiente et al., 2014). Plasmin additionally cleaves cell surface L1CAM in the cancer cells to suppress their ability to coopt the vasculature (Valiente et al., 2014). To evade astrocyte attack, brain metastatic cells from breast cancer and lung cancer express serpin inhibitors of plasminogen activator (PA) (Valiente et al., 2014). Although these observations indicate that astrocytes guard the brain against metastatic invasion, there is also evidence that the role of astrocytes in metastasis may not be uniformly antagonistic. In vitro, astrocyte co-culture protects melanoma cell lines from chemotherapeutic drugs (Kim et al., 2011), and in vivo astrocytes can activate Notch signaling in cancer cells (Xing et al., 2013).